Yao-Shan of traditional Chinese medicine: an old story for metabolic health

Type 2 diabetes mellitus, nonalcoholic fatty liver disease (NAFLD), cardio-cerebrovascular diseases (CCVDs), hyperuricemia and gout, and metabolic-related sexual dysfunction are metabolic diseases that affect human health in modern society. Scientists have made great efforts to investigate metabolic diseases using cell models in vitro or animal models in the past. However, the findings from cells or animals are difficult to translate into clinical applications due to factors such as the in vitro and in vivo differences; the differences in anatomy, physiology, and genetics between humans and animals; and the differences in microbiome–host interaction. The Chinese have extensively used the medicated diet of traditional Chinese medicine (TCM) (also named as Yao-Shan of TCM, Chinese Yao-Shan et al.) to maintain or improve cardiometabolic health for more than 2,200 years. These ancient classic diets of TCM are essential summaries of long-term life and clinical practices. Over the past 5 years, our group has made every effort to collect and sort out the classic Yao-Shan of TCM from the ancient TCM literature since Spring and Autumn and Warring States Period, especially these are involved in the prevention and treatment of metabolic diseases, such as diabetes, NAFLD, CCVDs, hyperuricemia and gout, and sexual dysfunction. Here, we summarized and discussed the classic Yao-Shan of TCM for metabolic diseases according to the time recorded in the ancient literature, and revised the Latin names of the raw materials in these Yao-Shan of TCM. Moreover, the modern medicine evidences of some Yao-Shan of TCM on metabolic diseases have also been summarized and emphasized in here. However, the exact composition (in terms of ratios), preparation process, and dosage of many Yao-Shan are not standardized, and their main active ingredients are vague. Uncovering the mystery of Yao-Shan of TCM through modern biological and chemical strategies will help us open a door, which is ancient but now looks new, to modulate metabolic homeostasis and diseases.


Introduction
Modern human society is encumbered by a pandemic of chronic diseases and conditions in which metabolic dysregulation plays a key role in the pathogenesis and progression (Newgard, 2017).These metabolic disorders may include obesity, type 2 diabetes mellitus (T2DM), nonalcoholic fatty liver disease (NAFLD), cardiocerebrovascular diseases (CCVDs), hyperuricemia and gout, metabolic-related sexual dysfunction, and complications associated with these diseases, which are collectively referred to as cardiometabolic diseases (CMDs) (Shi et al., 2015;Zhang et al., 2017a;Zhang et al., 2017b;Zhang et al., 2017c;Zhang and Li, 2017;Dehlin et al., 2020;Chen X. W. et al., 2021;Osborn et al., 2021;Zhang et al., 2021;Angulo and Hannan, 2022;Choi et al., 2022;Nappi et al., 2022;Zhang et al., 2022).Among CMDs, CCVDs remain the leading cause of disease burden worldwide (Roth et al., 2020).For example, there are about 330 million patients with CCVDs in China, which account for 46.74% and 44.26% of all deaths occurring in China's rural and urban areas: two out of five deaths were caused by CCVDs.The total hospitalization costs in China were 313.366 billion RMB for CCVDs in 2019 (China Cardiovascular Health and Disease, 2022).NAFLD, which is viewed as the hepatic manifestation of metabolic syndrome, is associated with obesity and encompasses a broad spectrum of conditions, from simple steatosis [always refers to nonalcoholic fatty liver (NAFL)], through nonalcoholic steatohepatitis (NASH), to fibrosis and cirrhosis, and ultimately hepatocellular carcinoma (HCC) (Samuel and Shulman, 2018;Zhang Y et al., 2020;Loomba et al., 2021).Moreover, NAFLD and T2DM frequently coexist as they share the same pathogenic abnormalities of excess adiposity and insulin resistance (Smith and Adams, 2011).Currently, 25% of the world population is thought to have NAFLD (Younossi et al., 2019;Lazarus et al., 2022), and the national prevalence of NAFLD in China has exceeded 29% (Zhou et al., 2019;Zhou et al., 2020).The estimated annual medical costs directly attributable to NAFLD have exceeded $103 billion in the United States and €35 billion in four European countries (Germany, France, Italy, and the United Kingdom) (Zhou et al., 2020).The pandemic of NAFLD fuels the upsurge in cardiovascular diseases (CVDs), and currently, NAFLD is emerging as an essential driver for CVDs, such as atherosclerosis, hypertension, and cardiac arrhythmia (Cai et al., 2020;Zhang L et al., 2020;Zhao et al., 2020;Chen Z. et al., 2021;Zhou et al., 2021;Li et al., 2022).CVDs are the leading cause of death in patients with NAFLD (Lazarus et al., 2022).In addition, metabolism dysfunction is recognized as a major contributor to diseases untraditionally considered "metabolic" in origin, such as cancer, cognitive disorders, and respiratory pathologies (Newgard, 2017).CMDs are difficult for physicians to manage because CMDs can be present for years before becoming clinically apparent (Roberts and Gerszten, 2013).Therefore, discovering the accurate predictors of CMDs, and prevention and treatment strategies, are of particular importance.
Although great efforts have been made by biological and medical scientists using cell or animal models to investigate the pathogenesis and treatment strategies for CMDs, these findings appear difficult to translate into humans due to the in vitro and in vivo differences; the differences between humans and animals in anatomy, physiology, genetics, and the differences in gut (also including vagina and others) microbiome-host interaction, among other factors (Łaniewski et al., 2020;Jardon et al., 2022).Currently, prevention or delay of the morbidity of CMDs is possible via pharmacological and behavioral interventions (e.g., weight control and diet modification) (Roberts and Gerszten, 2013;Morgan and Singh, 2021).However, most patients always do not accept long-term drug-lowering therapies due to a lack of compliance and, thus, exhibit a poor treatment response.Alternatively, they increasingly prefer non-classical pharmacological interventions (Morgan and Singh, 2021).Therefore, it will be beneficial if the daily diet has medicinal properties.This will not only satisfy human demand for material and energy, human yearning for delicious food, and use for social entertainment but, more importantly, also improve the quality of life and maintain human health.In the past 5 years, we have made every effort to collect and sort out medical diets from the ancient classic traditional Chinese medicine (TCM) literature.Here, we summarize the TCM diets for metabolic diseases according to the time of their recording in TCM literature.We also discuss the research progress of these diets using modern biological strategies.We hope these can provide beneficial references for the prevention and treatment of modern metabolic diseases.
Yao-Shan of TCM had been originally created by the Chinese for more than 2200 years; it is an important part of TCM.The word "Yao-Shan" was first described in "Hou Han Shu • Lie Nv Zhuan-74," dating back to before 445.Several early formed Yao-Shan of TCM have been recorded in medical literature unearthed from Ma-Wang-Dui Han Tombs in Changsha, China, such as "Yang Sheng Fang," "Za Liao Fang," "Tai Chan Shu," and "Wu Shi Er Bing Fang," which were formed before 168 BC.In ancient China, the government of each dynasty had officials in charge of medicated diet.For example, the department in the central government of Tang Dynasty specialized in supplying Yao-Shan for the imperial court was called "Shan Bu," and the department in charge of Yao-Shan in the central government of Qing Dynasty was called "Jing Shan Si." Yao-Shan of TCM has been extensively used by the Chinese in daily healthcare and in the treatment of human diseases based on the TCM theoretical system (e.g., diabetes, NAFLD, and other metabolic disorders).Moreover, Yao-Shan of TCM has wildly spread abroad, greatly impacting Japan, the Korean Peninsula, and the Association of Southeast Asian Nations.
Yao-Shan of TCM for Xiao-Ke (and/or diabetes) Diabetes mellitus primarily includes type 1 diabetes (T1D) and T2MD in modern medicine (Sims et al., 2021).T1D is a chronic autoimmune disease caused by the immune-mediated destruction of pancreatic β cells, resulting in lifelong absolute insulin deficiency (Atkinson et al., 2014;Warshauer et al., 2020).T2MD is characterized by relative insulin deficiency caused by pancreatic β-cell dysfunction and insulin resistance in target organs.The main drivers of T2DM are the rise in obesity, a sedentary lifestyle, an energy-dense diet, and population aging (Chatterjee et al., 2017;Zheng et al., 2018).Of the estimated 463 million adults with diabetes mellitus globally, >90% have T2DM, of which approximately 50% live in two large countries: India and China (Ke et al., 2022).
In TCM, diabetes mellitus belongs to the category of Xiao-Ke and others.Xiao-Ke was first recorded in Qi-Bing-Lun Section 47 from the classic TCM literature Huang Di Nei Jing • Su Wen (Wang and Cheng, 1999;Chen et al., 2002;Wu, 2002;Lv, 2006;Chen et al., 2015;Tong, 2016).It has been considered that the symptoms of Xiao-Ke are characterized by excessive urination, excessive drinking water, excessive diet consumption (the regular food that a person eats each day), and weight loss.All these are collectively referred to as "three excessive and one loss" (Tong et al., 2012;Chen et al., 2015) (Figure 1).Turbid or sweet urine is also an essential feature of Xiao-Ke (Tong et al., 2012;Chen et al., 2015).The main pathogenesis of Xiao-Ke is yin deficiency and endogenous drynessheat in body, these two always mutually influence each other, the above two can be induced by unhealthy diet, emotional disorder, and excessive sexual activities (Tong et al., 2012;Chen et al., 2015;Pang et al., 2015).If prolonged yin deficiency impairs yang, dual deficiency of qi ("qi" is a broad TCM concept, generally refers to "the most basic substances that maintain human life activities") and yin, as well as dual deficiency of yin and yang, will occur (Pang et al., 2015).In addition, blood stasis is also involved in the pathogenesis of Xiao-Ke.Therefore, the basic therapeutic methods for Xiao-Ke are invigorating qi (supplement qi), nourishing yin, clearing heat, and promoting fluid production (generating body fluids) (Pang et al., 2015).
Since ancient times, the Chinese have realized that the combination of some daily feeding diets may cause Xiao-Ke.Huang Di Shi Jin described that eating "Fanlou {also as Fanluo, Stellaria media (L.) Vill.[Caryophyllaceae]}" with "Yu-Shan-Zha (a kind of salted fish)" can induce Xiao-Ke.Yang Sheng Yao Ji written by Zhang Zhan in the Chinese East Jin (or North Wei) Dynasty revealed that eating Yu-Zha (also as a kind of salted fish) with Dou (it refers to beans, however, the details are unclear) may induce Xiao-Ke.Similarly, Sun Zhen Ren Shi Ji, written by Sun Simiao in the Chinese Tang Dynasty, further described that eating Chidou {also as Chixiaodou, Vigna angularis (Willd.)Ohwi & H.Ohashi [Fabaceae; Vignae semen], Vigna umbellata (Thunb.)Ohwi & H.Ohashi [Fabaceae; Vignae semen]} or Baidou (the plant and its corresponding Latin name it refers to are yet to be verified) combined with Yuzha may also induce Xiao-Ke.Both San Yuan Can Zan Yan Shou Shu (written by Li Pengfei in the Chinese Yuan Dynasty) and Shi Jin Fang reported that "eating the roast meat of Chinese water deer {Hydropotes inermis Swinhoe [Cervidae]} may cause Xiao-Ke."San Yuan Can Zan Yan Shou Shu also showed that "eating uncooked dog meat may cause Xiao-Ke."Similar to this, Ben Cao Yue Yan, written by Xue Ji in the Chinese Ming Dynasty, stated that "eating the roast meat of yellow dog may cause Xiao-Ke."Importantly, Xue Ji also revealed that alcohol may cause Xiao-Ke.Zhang Zhan had showed that "eating wheat with Gumi {the caryopsis of Zizania latifolia (Griseb.)Turcz.ex Stapf.
[Gramineae]}, then, drinking alcohol will lead to Xiao-Ke".Li Pengfei had described "if an unawakened drunk feel great thirst, then, he drinks cold water and cold tea, cold will be introduced into the kidney by the wine, and become cold poison; if much and long, it will cause heavy of waist and knees (and foot), cold pain of bladder, edema, Xiao-Ke and Luanbi".This was also reported by Wu Zhenglun from the Chinese Ming Dynasty in Yang Sheng Lei Yao.However, it is not clear whether the above factors can cause Xiao-Ke in humans, who live in modern society.If so, what is the mechanism behind these changes, and further exploration is needed.
In contrast, the Chinese had used ancient classic TCM prescriptions, or even a single Chinese medicinal material, and the TCM diets to treat Xiao-Ke for more than 2,200 years, for example, Huang Di Nei Jing • Su Wen showed Xiao-Ke can be treated by "Lan {it may refer to Peilan, Eupatorium fortunei Turcz.
[Asteraceae]}" through its ability to eliminate "Chen Qi".Here, we summarize and discuss these ancient classic TCM diets according to their publishing time.Some of these discussed ancient classic TCM diets have been recorded repeatedly in the following ancient literature, indicating that they may undergo more clinical practices.
Qi Juan Shi Jing described that Gugen {rhizome and root of Zizania latifolia (Griseb.)Turcz.ex Stapf.[Gramineae]} and Fanlou may improve Xiao-Ke.However, we do not know why eating Fanlou with Yu-Shan-Zha may induce Xiao-Ke, whereas eating Fanlou alone is beneficial for Xiao-Ke.As Yu-Shan-Zha is a regular diet in China, it is urgent to answer the mechanisms of these differences.
Cui Yu Xi Shi Jing, written by Cui Yuxi in the Chinese Jin Dynasty, reported that Kuicai {Malva verticillata L. [Malvaceae]} (Wei, 1964;Ma and Wang, 2016), Shichun {Ulva lactuca L. [Poaceae]}, the deer's head and meat, Shi-Yin-Zi, Long-Ti-Zi, and He-Bei-Zi (however, the biological or mineral sources of the later three still need further investigation), were the representative Yao-Shan for alleviating Xiao-Ke.Some of these Chinese Yao-Shan for Xiao-Ke were further confirmed by modern medicine.The polysaccharides from Ulva lactuca L. [Ulvaceae] (ULP, 180 mg/kg per day for 30 days by oral gavage) improve antioxidant balance and bone mineral density in alloxan-induced diabetic Wistar rat model, and the low dose of ULP (100 mg/kg) significantly alleviated hyperglycemia and glucose tolerance impairment in diabetic mice caused by D-gal and streptozotocin (STZ) with a high-sugar, highfat diet (Sahla et al., 2021;Chen et al., 2022).One clinical trial showed that drinking fruit juice of Actinidia chinensis Planch.
[Actinidiaceae] (10 ml per day) for nine months, and combined with exercise (each patient walks about 1.5 to 2 miles per day), improves anti-oxidative and anti-inflammatory status of T2DM patients by activating Kelch-like ECH-associated protein 1 (Keap1) and nuclear factor erythroid-derived 2-like 2 (Nrf2) via increasing microRNA-424 (Sun et al., 2017).Feeding the basal diet mixed with 5% (w/w) dietary fibers from bamboo shoot shells to diabetic mice induced by HFD plus STZ for four weeks display the hypoglycemic effect (Zheng et al., 2019).The β-pyran polysaccharides from bamboo shoot shells (400 mg/kg per day for 3 weeks by oral gavage) may be responsible for this hypoglycemic activity (Zheng et al., 2016).Although there are no direct experimental data of the deer's head or meat on diabetes, the 5-10 kDa peptides from red deer {Cervus elaphus L. [Cervidae]} antler (intraperitoneally, 75, 150, or 300 μg/kg per day for 6 weeks) showed hypoglycemic, hypolipidemic, and antioxidant effects in diabetic mice induced by STZ (Jiang et al., 2015;Wang W et al., 2019).In addition, a new bioactive peptide CPU2206 from sika {Cervus nippon Temminck [Cervidae]} antler also alleviated diabetes in alloxan-induced diabetic mice and in obese mice with spontaneous diabetes (KK-Ay mice) (CPU2206, intraperitoneally, 30 or 100 mg/kg; once a day for 28 days in the first animal model, and once a day for 14 days in the second animal model) (Jiang et al., 2015;Wang W et al., 2019).These two studies have confirmed the anti-diabetes effect of the peptides from the antlers.However, antlers and its products are rarely administered by intraperitoneal injection in the clinical practice of TCM.The antlers are often administered orally, so it is more meaningful to study antlers from the perspective of oral administration in future.
Sun Zhen Ren Shi Ji stated that soaking the meat of Xian {a species of small clam living in fresh water, it may refer to Corbicula fluminea Müller [Corbiculidae]} in water and drinking it has a therapeutic effect on Xiao-Ke.The antidiabetic components of Corbicula fluminea Müller [Corbiculidae] include phytosterols and fatty acids (Huang et al., 2022a), a polysaccharide-protein complex (Wang Y Y et al., 2019), and peptides (Huang et al., 2022b).Clinical data showed that consumption of 2 g of the Corbicula fluminea Müller [Corbiculidae] extract daily for 180 days reduces serum TNF-α levels in pre-diabetic patients in the Taiwan province of China (Huang et al., 2022a).Similar to Shen Nong Ben Cao Jing, Sun Zhen Ren Shi Ji described Fuping as a benefit for Xiao-Ke.
Meng Shen Shi Jing reported that the boiled juice (or soup) of Mazi {the mature seeds of Cannabis sativa L. [Cannabaceae] with shell}; the boiled juice (or soup) of the shell of Chinese chestnut {the fruits of Castanea mollissima Blume [Fagaceae]}; the boiled juice (or soup) of Lüdou {the mature seeds of Phaseolus radiatus L. [Fabaceae]}; and the soup of the meat from head of donkey have antidiabetic effects on Xiao-Ke.Clinical data showed that cannabis use was associated with a lower risk of diabetes in chronic hepatitis C-infected patients (Barré et al., 2020).Orally administrated phenolic extracts from burs of Chinese chestnut at doses of 150 or 300 mg/kg twice a day for 12 days exhibited potential antidiabetic activities in STZ-induced diabetic rats (Yin et al., 2011).In addition, the former antidiabetic Yao-Shan, such as Wuyu, Linqin, and the meat of deer's head, were also reported in Meng Shen Shi Jing.
[Brassicaceae]} were essential Yao-Shan for Xiao-Ke.In animals, the juice of the root of Raphanus sativus L. [Brassicaceae] (300 mg/kg, a single oral treatment) showed a hypoglycemic effect in STZ-induced diabetes in Wistar rats (Shukla et al., 2011).Flavonoid-rich wheatgrass {Triticum aestivum L.
[Poaceae]; used wheatgrass extract at 9 th days after germination, 200 or 400 mg/kg per day for 60 days} diet attenuated diabetes induced by STZ plus HFD in Wistar rats (Adhikary et al., 2021).Sulfated polysaccharides (CCPS) from Cipangopaludina chinensis Gray [Viviparidae] (100 or 400 mg/kg per day for 12 weeks) attenuated atherosclerosis in high fat diet (HFD)-fed ApoE −/− mice (Xiong et al., 2019).However, its effects on diabetes are unclear, and the water soaked in Cipangopaludina chinensis Gray [Viviparidae] might not contain contents such as CCPS, therefore, the mechanisms of Tian-Zhong-Luo on Xiao-Ke still need further investigation.Additionally, Zan Yin also described bamboo shoots and Sumi for Xiao-Ke, which have already been reported in the earlier Yao-Shan literature.
[Poaceae], or Setaria italica (L.) Beauv.var.germanica (Mill.)Schred.[Poaceae]; if the mature seeds stored for a long time, they called "Chen-Su-Mi"}, Qing-Xiao-Dou (it may refer to Lüdou), Sha-Niu-Sui (the bone marrow of female cattle), the meat of female cattle, and the meat of yellow hen are the representative Yao-Shan for Xiao-Ke.The hydroalcoholic extract of Hordeum vulgare L. [Poaceae] (0.25, 0.5 g/kg per day for 11 days by oral gavage) and the seeds extract of Setaria italica (L.) P.Beauv.
[Poaceae] (25%, 45%, or 65% whole grain highland barley in diets) for 8 weeks displayed antidiabetic effects in db/db mice (Deng et al., 2020).In healthy Japanese, the consumption of a meal containing refined barley (refers to Damai) flour bread is associated with a lower postprandial blood glucose concentration after a second meal compared with one containing refined wheat flour bread (Matsuoka et al., 2020).Bottle gourd {Lagenaria siceraria (Molina) Standl.[Cucurbitaceae]} is advocated for diabetes in Ayurveda.However, toxic cucurbitacins in bitter bottle gourd should be considered (Verma and Jaiswal, 2015).Furthermore, Bei Ji Qian Jin Yao Fang described the former reported Yao-Shan, including Shichun, Wuyu, Song, bamboo shoot, and the meat from deer's head, for Xiao-Ke.
Tai Ping Sheng Hui Fang, written by Wang Huaiyin et al. in the Chinese North Song Dynasty, described many Yao-Shan for Xiao-Ke.
Here, we discussed seven Yao-Shan with the specific Chinese name.
[Rosaceae]} kernels, the milk of cow, Damai, and the white granulated sugar can also be added.( 5).Yang-Fei Geng Fang includes the Yangfei {lung of Capra hircus L. [Bovidae], Ovis aries L. [Bovidae]}, mutton, the polished round-grained rice {the mature seeds of Oryza sativa L. [Poaceae]}, Congbai,ginger,salt,and vinegar et al. (6).Huang-Ci-Ji Zhou Fang (Huang-Ci-Ji refers to the meat of yellow hen).( 7).Shen Xiao Zhu Tu Fang (Tu refers to rabbit) mainly includes the rabbit and the fresh Sangbaipi {Morus alba L. [Moraceae]}.Moreover, this literature also described the deer's head, Zhi, Tian-Zhong-Luo, and Luobo, for alleviating Xiao-Ke, and these have always been reported in the earlier Yao-Shan literatures.Although the cooking methods of above Chinese Yao-Shan have been mentioned in Tai Ping Sheng Hui Fang, however, further clinical and animal experiments are still needed to confirm whether they are suitable for treating Xiao-Ke in modern society.
Feng Qin Yang Lao Shu, written by Chen Zhi in the Chinese North Song Dynasty, described Niuru Fang (Niuru refers to the milk of cow), Qing-Liang-Mi Yin Fang, Qingdou Fang (Qingdou may refer to Lüdou), Donggua Geng Fang, Lutou Fang (Lutou refers to the deer's head), Zhudu Fang (Zhudu refers to the pig stomach), and Lugen Yin Fang {Lugen refer to the rhizome of Phragmites communis Trin.[Poaceae]}, were used for alleviating Xiao-Ke.These Yao-Shan were mainly used by drinking juice or eating them after cooking.The key ingredients in the former five Fangs have already been discussed above.Lugen (ethanol extract, 5.0 g/kg per day for 5 weeks; polysaccharide solution of Lugen, 100 mg/kg per day for 3 weeks; given orally by gavage) has antidiabetic effects in STZ-induced diabetic mice (Zhang et al., 2011;Cui et al., 2012;Xu et al., 2012;Song et al., 2014;Zheng et al., 2017).The seven Yao-Shan above have also been reported by Hong Pian from the Chinese Ming Dynasty in Shi Zhi Yang Lao Fang.
The antidiabetic effects of yam was further confirmed in HFD plus STZ-induced diabetic mice by treating with yam aqueous extract (500 or 1000 mg/kg yam aqueous extract per day for 4 weeks by oral gavage) or its active component allantoin (20 or 50 mg/kg per day for 4 weeks by oral gavage) (Ma et al., 2020).Supplement of allantoin by intravenous injection (0.5 mg/kg, 3 times per day for 3 or 5 days) had marked plasma glucose-lowering action and increased insulin sensitivity in STZ-induced diabetic rats; these actions were blocked by specific imidazoline I-2 receptors (I-2R) antagonist, BU224.The activated I-2R enhanced the release of β-endorphin from the adrenal gland and then promoted AMPK phosphorylation and glucose transporter type 4 (GLUT4) expression in the muscle.All these contribute to the glucose-lowering action of allantoin in STZinduced diabetic rats (Niu et al., 2010;Lin et al., 2012).Go et al. (2015).Hyeon-Kyu Go et al. had compared the antidiabetic activity of crude yam powder, water extract of yam, and allantoin in STZ-induced diabetic rats.They found that the water extract of yam (500 mg/kg per day for 31 days by oral gavage) exerted a stronger antidiabetic effect than allantoin.The other constituents of yam (e.g., polysaccharides, dioscorin, sapogenins, choline, l-arginine, and proteins) may be responsible for the better effect of water extract of yam on diabetic rats (Go et al., 2015).Some of these contents have beneficial effects on diabetes.The Chinese yam-derived polysaccharide has a hypoglycemic effect in HFD and high sugar diet plus STZ-induced diabetic C57BL/6 mice model (200 mg/kg acidic polysaccharide daily for 5-6 weeks by oral gavage) (Feng et al., 2022), in a high-energy diet combined with dexamethasone-induced diabetic mice model (50, 100, or 150 mg/kg per day for 35 days by oral gavage) (Li et al., 2017), in alloxan-induced diabetic rat model (fed rats with nano yam polysaccharide of 50 or 100 mg/ml per day for 12 days), and in HFD-induced hyperlipidemia rat model (fed rats with nano yam polysaccharide of 50 or 100 mg/ml per day for 30 days) (Yu et al., 2020).Interventions of yam dioscorin (80 mg/kg per day by oral gavage) for 135 days reduced weight gains and improved the impaired glucose tolerance in HFD-fed C57BL/6J mice (Wu et al., 2018).
In T2DM patients, yam gruel therapy (the concentration used is 0.5 g/mL made by 150 g yam and 300 mL water, taking yam gruel daily in the morning for 12 weeks) reduces fasting blood glucose and 2-hour postprandial blood glucose with the actions of modulating gut microflora, increasing the serum levels of superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px), while decreasing blood high-sensitivity C-reactive protein (hs-CRP) and serum interleukin-6 (IL-6) levels (Pang et al., 2017a;Pang et al., 2017b;Pang et al., 2017c;He et al., 2022).Moreover, treatment with yam gruel (250 mL per day in the morning, 5 times per weeks for 10 weeks) also decreases blood glucose and improves insulin resistance in female patients with gestational diabetes mellitus, while the pregnancy outcomes have no obvious influence (Zhao et al., 2021).We expect large scale clinical trials to verify the efficacy, dosage, and key molecular mechanisms of yam gruel on diabetes.

Yao-Shan of TCM for nonalcoholic fatty liver disease
NAFLD is a metabolic disease representing the hepatic manifestation of a systemic metabolic disorder (Tilg and Effenberger, 2020).In the ancient TCM literature, there is no clear record of "NAFLD."It belongs to different categories such as "liver stuffiness," "pain in the subcostal region," and "masses".
The key pathogenesis of NAFLD is generally related to the abnormal free flow of qi by the liver, dysfunction of transportation and transformation by the spleen, and loss/deficiency of the kidney essence.All of these lead to the mutual accumulation of dampness, heat, phlegm, and blood stasis in the liver, thus forming NAFLD.The TCM methods of drying dampness and resolving phlegm, promoting blood circulation and resolving blood stasis, strengthening spleen and promoting digestion, are common strategies used to treat NAFLD.
Shanzha {Crataegus pinnatifida Bunge [Rosaceae; Crataegi fructus], Crataegus pinnatifida var.major N.E.Br.[Rosaceae; Crataegi fructus]} has been commonly used as a traditional medicine in Asia (such as China, Korea, and Japan), and also as an essential Chinese diet (Yao-Shan) (Hussain et al., 2021).Based on the TCM theory, Shanzha can promote digestion and strengthen the spleen, circulate qi and disperse stasis, and transform turbidity and lower lipid.Therefore, Shanzha is a well example Yao-Shan of TCM for alleviating NAFLD.Clinically, long-term high-dose consumption of boiled hawthorn juice can reduce blood lipids in patients with NAFLD (Tao, 2021).The Shanzha extracts, such as vitexin [1, 10, or 20 mg/kg per day for 8 weeks by oral gavage; daily injected 6 mg/kg for 4 weeks; 200 mg/kg Shanzha extract (its key ingredient is vitexin) per day for 8 weeks by oral gavage]; procyanidins (50, 100 or 200 mg/kg per day for 8 weeks by oral gavage); and pectin pentaoligosaccharide (150 mg/kg per day for 10 weeks by oral gavage), have the abilities to attenuate obesity-induced NAFLD in HFD-fed animals partially by increasing the expression and activities of hepatic fatty acid oxidation-related enzymes, activating AMPK and autophagy, and modulating gut microbiota (Li et al., 2013;Inamdar et al., 2019;Hussain et al., 2021;Han X et al., 2022;Jiang et al., 2022).Another component corosolic acid (10 or 20 mg/kg per day for 9 weeks by oral gavage) from Shanzha alleviated carbon tetrachloride (CCl 4 ) plus HFD-induced NASH in mice by inhibiting TGF-β1/Smad2, NF-κB, and AMPK signaling (Liu G et al., 2021).According to the TCM theory, the TCM formula can increase efficiency and reduce toxicity.Therefore, Shanzha has also been used in the TCM formula for treating NAFLD and alcoholic liver disease (ALD).One   Yao-Shan of traditional Chinese medicine (Yao-Shan of TCM) for metabolic health and diseases.The traditional Yao-Shan of TCM always includes soup, congee, and drinks.They have been used for treating Xiao-Ke, which is characterized by excessive urination, excessive drinking water, excessive diet consumption, and weight loss; fatty liver diseases (FLDs, including NAFLD and ALD); cardiovascular diseases (CVDs); hyperuricemia and gout; and male and female sexual dysfunction.However, prescribing a Yao-Shan of TCM is more complicated than prescribing a pill.It should be prescribed and prepared with the guidance of the TCM theory and the cooking theory.Yao-Shan of TCM will open a door, which is ancient but now looks new, to modulate metabolic homeostasis and diseases.(Kwon et al., 2005).NAFLD and other metabolic diseases are always related to unhealthy dietary habits, in turn, Yao-Shan of TCM provides a unique and alternative way to solve metabolic problems from the perspective of dietotherapy.

Yao-Shan of TCM for other metabolic disorders
In addition to diabetes and NAFLD, the Chinese have a long history of using Yao-Shan of TCM to treat other metabolic disorders, such as CCVDs, sexual dysfunction, and gout.Here, we show examples of these.Ling Shu • Wu Wei reported that "a patient with heart disease should eat Mai, mutton, apricot, and Xiebai, but avoid the salty food."Huang Di Shi Jin noted that "a mustang penis is sour, salty, warm and non-toxic, it treats male penile atrophy, oligospermia."Shi Liao Ben Cao showed that "making the egg white of sparrow eggs, Tianxiong {the root tuber of Aconitum carmichaelii Debeaux [Ranunculaceae]; powder}, and Tusizi {Cuscuta australis R.Br.[Convolvulaceae; Cuscutae semen], Cuscuta chinensis Lam.[Convolvulaceae; Cuscutae semen]; powder} as pills, take 5 pills with wine on an empty stomach, these can treat male sexual impotence, female leucorrhea, defecation adverse."The Chinese had accumulated a lot of Yao-Shan of TCM for sexual health in ancient times.However, how they worked remains a mystery.Yao-Shan of TCM has also emerged as essential means for hyperuricemia and gout, e.g., the juice from fruit of Mei {Prunus mume (Siebold) Siebold & Zucc.[Rosaceae]} (500 mg/kg per day for 4 weeks by oral gavage) promotes uric acid excretion via modulating the expression of renal and intestinal urate transporters in mice with adenineinduced chronic kidney disease (Huang et al., 2022c).Based on the TCM theory, we should consider TCM diets such as nourishing yin and clearing heat for hyperuricemia and/or gout patients.However, if we do not consider the levels of purine in original materials of Yao-Shan, it obviously does not conform to modern medical theories and treatment principles.Therefore, the arrangement of Yao-Shan should not only consider the TCM theory, but also consider the characteristics of nutrients of these raw materials and even the whole Yao-Shan of TCM after cooking.

Perspective
When discussing metabolic diseases, patients are always advised to control their diet.On the contrary, Yao-Shan of TCM will tell patients what they can eat (Figure 1).After being processed, many raw materials of the Chinese Yao-Shan have been used as drugs in TCM prescriptions.Here, their roles are drugs, not food.Under the guidance of TCM theory and cooking techniques, these raw materials can be made into food or drink, which have the characteristics of dual use of medicine and food.Here, their roles are not only effective to prevent and treat human diseases, however, most importantly, most of them are also delicious and palatable dishes.Therefore, they have always been favored by people, especially those with metabolic disorders.
The Chinese Yao-Shan (dietotherapy), an old discipline created by the Chinese, is an important part of TCM.It is indisputable that the Yao-Shan of TCM has a huge impact on human mental and physical health, not limited to CMDs.In the United States and elsewhere, governments, non-profit organizations, and companies have also pledged huge funds to investigate Food As Medicine (2023).However, there are fundamental differences in the logical construction between Yao-Shan of TCM and Western dietetics: the former is based on the idea of yin and yang and nature-human interaction and has a holistic view, while the latter regards the life characteristics of the human body as the process of chemical reaction, and the problems can be corrected and changed by chemical methods.Hence, prescribing a Chinese Yao-Shan is more complicated than prescribing a pill.The development of Yao-Shan of TCM should be guided by both the TCM theory and the cooking theory.If it is separated from the guidance of these theories, this ancient discipline will lose its source of vitality.Moreover, our lifestyles (concerning, e.g., the gut and vagina microbiome) are much different from those of ancient times.Therefore, the effects and mechanisms of this classic dietotherapy of TCM should be further confirmed in clinic and animal models.
Huang Di Nei Jing, Shen Nong Ben Cao Jing, San Yuan Can Zan Yan Shou Shu, Yang Sheng Lei Yao, and Ben Cao Yue Yan, the original texts of other above TCM literature have been lost.The details of some above Yao-Shan were reprinted in Bei Ji Qian Jin Yao Fang by Sun Simiao in the Chinese Tang Dynasty, Zheng He Ben Cao by Tang Shenwei and Yang Sheng Lei Zuan by Zhou Shouzhong both in the Chinese South Song Dynasty, Shi Jian Ben Cao by Fei Boxiong in the Chinese Qing Dynasty.Many ancient Japanese medicine was learned from China, some of these original texts were also partially reprinted in Wo Ming Lei Ju Chao by Yuan Shun (Japanese) in the middle of 10th century of Japan, Yi Xin Fang formed in 984 AD by Dan Bo Kang Lai (Japanese), Wei Sheng Mi Yao Chao formed in 1228 AD by Dan Bo Xing Zhang (Japanese), and Wan An Fang formed in 1315 AD by Wei Yuan Xing Quan (Japanese).